Radiation therapy, also known as radiation oncology, is the general term for any treatment involving medical use of ionizing radiation to destroy malignant cells. Radiation therapy affects malignant tissue cells by damaging cells' DNA by either a direct or indirect ionization of the atoms that make up the DNA chain.
Indirect ionization refers to the ionization of water, which leads to the formation of free hydroxyl radicals that damage the DNA. This type of ionization is typically achieved by the use of photon energy. Direct ionization occurs via direct energy transfer from the charged particles, such as proton, boron, carbon or neon ions, to the cancerous cells, thereby causing breaks in the cells' double-stranded DNA.
One of the most common problems encountered during the radiation therapy of malignant tumors is that the tumor cells become deficient in oxygen—a condition referred to as hypoxia. Hypoxia commonly develops within solid tumors because tumor cell growth is greater than the rate of blood vessel formation. Thus, the increase in tumor mass results in inadequate vasculature formation, which compromises the blood supply. The exposure of tumor cells to a hypoxic environment is associated with angiogenesis, metastasis, radiation resistance, and drug resistance.
It is presently known that oxygen deficiency influences some major intracellular pathways, such as those involved in cell proliferation, cell cycle progression, apoptosis, cell adhesion, and others. When investigating the effects of radiotherapy or chemotherapy under hypoxic conditions, it is essential to consider the influences of hypoxia itself on the cell.
Chronic hypoxia, also referred to as “diffusion-limited” hypoxia, typically occurs in the areas of large intervascular distances that are beyond the diffusion limit of oxygen (i.e., approximately >150 μm). However, the origins of the chronic hypoxia are more complex. Compared with normal tissue vessels, the tumor microvasculature commonly shows characteristic structural and functional abnormalities. Tumor blood vessels display a highly irregular vascular geometry with arteriovenous shunts, blind ends, lack of smooth muscle or enervation, and incomplete endothelial linings. Additionally, the abundant proliferation of tumor cells results in a disturbed balance between oxygen supply and demand. Furthermore, a relative lack of arteriolar input into tumors creates severe longitudinal oxygen partial pressure (pO2) gradients within the vessels themselves. All of these features contribute to the fact that a great portion of tumor cells are situated in chronically hypoxic regions.
An acute hypoxia, or so-called “perfusion-limited” hypoxia, is typically caused by spontaneous fluctuations in tumor blood flow, which produce temporary regions of acute hypoxia. These fluctuations result from transient occlusion and narrowing of vessels and arteriolar vasomotion.
One important issue to consider in any anticancer therapy is in what proportions both types of hypoxia, acute and chronic, are present in human tumors. In the past, chronic hypoxia has always been considered as the most important factor. However, studies have now demonstrated that microregional fluctuations in erythrocyte flow, consistent with transient, perfusion-driven changes in oxygenation, which are the signs of acute hypoxia, are also a common feature of human malignancies. Therefore, it has to be taken into account that both types of hypoxia occur commonly in human tumors.
Oxygen is an essential radiosensitizer during the radiation therapy. The presence of oxygen at the time of irradiation increases the effectiveness of a given dose of radiation by forming DNA-damaging free radicals. During the radiation therapy, a direct ionization or reaction of the radiation with hydroxyl radicals produced by radiolysis of nearby water molecules result in a formation of DNA radicals. Oxygen, which has a very high electron affinity, reacts extremely fast with the free electrons of these radicals, thereby fixing the free radical damage. However, in the absence of oxygen, reducing compounds interact with the DNA radicals by hydrogen donation. This interaction leads to restitution of the DNA to its undamaged state. As a result, hypoxia severely compromises ionizing radiation in its ability to kill malignant cells.
The radio-resistance of hypoxic cells is a serious limitation in attempts to increase the therapeutic ratio between tumor and normal tissue damage in radiotherapy. This disadvantage of hypoxic cells is somewhat reduced in tumors which can reoxygenate their hypoxic cells during fractionated radiotherapy, for example, by shrinkage.
Much research has been devoted to overcoming hypoxia in conjunction with anticancer therapies. Presently known methods of overcoming hypoxia include the use of high pressure oxygen tanks, blood substitutes that carry increased oxygen, radiosensitizing drugs, such as misonidazole and metronidazole, and hypoxic cytotoxins, such as tirapazamine. However, these known methods suffer from a number of significant drawbacks.
One of the major drawbacks of the prior art methods of reversing hypoxia is that the radiosensitizing drugs are typically delivered intravenously. This causes overoxygenation of various bodily tissues which can lead to serious organ damage and even organ failure. For example, doxorubicin, which is commonly used in the treatment of a wide range of cancers and is typically administered intravenously in the form of hydrochloride salt, is highly cardiotoxic, meaning that it causes oversaturation of oxygen in the heart tissue, leading to heart attacks.
Another major drawback of the known methods of overcoming hypoxia is that it usually takes a significant amount of time for the oxygenating agent to reach and absorb into target tumor tissue. This makes it difficult to determine the optimal time for exposing the tumor tissue to radiation to ensure an effective radiotherapy treatment.
Photodynamic therapy has been found effective at treating tumors locally. An especially effective method of photodynamic therapy has been in combination with the use of photosensitizing drugs. However, photodynamic therapy when used, exclusively, and when used in combination with photosensitizing drugs has been found to produce only superficial penetration into the tumor and/or target tissue. Consequently, photodynamic therapy has not been found to be a reliable, long-term curative solution.
Hence, there is a significant need for a method of treatment of hypoxic malignant tumors that is capable of delivering an oxygenating agent directly to tumor tissue in a bodily cavity to ensure more precise and efficient oxygenation of the target tumor site and to avoid exposing surrounding healthy tissue to potentially damaging chemical agents. There is also a need for a method of treatment of hypoxic tumors that allows for a synchronized oxygenation and radiation of tumor tissues to provide a highly effective anticancer therapy. It is also desired to provide a method of treatment of hypoxic tumors that combines radiation and photodynamic therapies. There is further a need to provide a method for treatment of hypoxic tumors wherein absorption of an oxygenating agent can be observed and monitored to ensure the optimal oxygen saturation in tumor tissue.